1,n6-etheno-5&#39;-adenosine carboxamides

ABSTRACT

AMIDES OF 1,N6-ETHENO-5&#39;&#39;-ADENOSINE CARBOXYLIC ACID REPRESENTED BY THE FORMULA   3-(2-(R1-N(-R2)-CO-),3-(R3O-),4-(R4O-)-TETRAHYDROFUR-5-YL)   -3H-IMIDAZO(2,1-I)PURINE   WHEREIN R1 AND R2 EACH ARE HYDROGEN, LOWERALKYL, LOWER ALKENYL LOWERALKYNYL OR CYCLOALKYL, AND R3 AND R4 EACH ARE HYDROGEN, ACYL, OR R3 AND R4 TAKEN TOGETHER FORM AN ISOPROPYLIDENE OR BENZYLIDENE MOIETY; AND THE PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF. THE COMPOUNDS WHEREIN R3 AND R4 ARE HYDROGEN ARE USEFUL IN TREATING CARDIOVASCULAR DISORBDERS AND ARE PARTICULARLY USEFUL AS ANTI-ANGINAL AND ANIT-HYPERTENSIVE AGENTS. COMPOUNDS WHEREIN R3 AND R4 ARE ACYL OR WHEN TAKEN TOGETHER FORM AN ISOPROPYLIDENE OR BENZYLIDENE MOIETY ARE INTERMEDIATES USEFUL IN THE PREPARATION OF THE FINAL PRODUCTS. (R3 AND R4=HYDROGEN.)

1,N -E'I'HEN0-5'-ADENQSINE CARBOXAMIDES Raj Nandan Prasad, Pierrefonds, Quebec, and David Lyon Garmaise, Montreal, Quebec, Canada, assignors to Abbott Laboratories, North Chicago, Ill. No Drawing. Filed Dec. 21, 1972, Ser. No. 317,326 Int. Cl. C07d 51/54 U.S. Cl. 260211.5 R 4 Claims ABSTRACT OF THE DISCLOSURE Amides of 1,N -etheno-5'-adenosine carboxylic acid represented by the formula wherein R and R each are hydrogen, loweralkyl, loweralkenyl loweralkynyl or cycloalkyl, and R and R each are hydrogen, acyl, or R and R taken together form an isopropylidene or benzylidene moiety; and the pharmaceutically acceptable acid addition salts thereof.

The compounds wherein R and R are hydrogen are useful in treating cardiovascular disorders and are particularly useful as anti-anginal and anti-hypertensive agents. Compounds wherein R and R are acyl or When taken together form an isopropylidene or benzylidene moiety are intermediates useful in the preparation of the final products. (R and R =hydrogen.)

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to adenosine derivatives, to therapeutic compositions containing such derivatives, to methods of preparing and using the novel compounds and to intermediates useful in the preparation of such compounds.

The compounds of this invention are represented by the formula wherein R and R each are hydrogen, loweralkyl, loweralkenyl, loweralkynyl or cycloalkyl, and R and R each are hydrogen, acyl, or R and R taken together form an isopropylidene or benzylidene moiety; and the pharmaceutically acceptable acid addition salts thereof.

The term loweralkyl as used herein, refers to both straight and branched chain alkyl radicals containing from 1 to 6 carbon atoms, including methyl, ethyl, npropyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, iso-butyl, n-pentyl, iso-pentyl, neo-pentyl, n-hexyl and the like.

Loweralkenyl refers to the C and C alkyl groups, as defined above, from which a hydrogen atom has been removed from each of two adjacent carbon atoms to pro- United States Patent 0 ice duce ethylenic unsaturation; e.g., vinyl, allyl, methallyl, l-pentenyl and the like.

Loweralkynyl refers to the C to C alkyl groups as defined above, from which 2 hydrogen atoms have been removed from each of two adjacent carbon atoms to produce acetylenic unsaturation such as ethynyl, propargyl, 2-butynyl, l-pentynyl and the like.

The term cycloalkyl refers to C and C cycloalkyl groups, namely, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

The term pharmaceutically acceptable acid addition salts refers to non-toxic salts prepared by reacting the amide with the appropriate organic or inorganic acid, or by utilizing an acid addition salt of the appropriate intermediate. Representative salts include the hydrochloride, hydrobromide, sulfate, bisulfate, acetate, valerate, oleate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, succinate, tartrate, napsylate and the like.

The term acyl refers to acetyl, propionyl, butyryl and the like.

The compounds of this invention are useful as antianginal agents at dosages of from 0.1 to 10 mg./kg. of body weight daily.

The anti-anginal activity was first established by measuring the increase in coronary sinus partial pressure of oxygen (p0 according to the method of Schoepke et al., Pharmacologist, 8, 204 (1966).

In addition to their cardiovascular activity, the compounds also exhibit central nervous system depressant activity at dosages of from 0.1 to 10 mg./kg. of body weight in test animals.

Generally speaking, the compounds of this invention are prepared by reacting the corresponding adenosine-5'- carboxylic acid ester with chloroacetaldehyde. The amides can be prepared by converting 2',3'-isopropylidene adenosine-5-carboxylic acid (prepared from 2',3'-isopropylidene adenosine according to the method described by Harmon et al., Chem. Ind., 1969, 1141) to the corresponding acid chloride, and reacting the acid chloride with an appropriate amine of the formula R R NH, followed by hydrolytic cleavage of the isopropylidene group, according to the following reaction scheme:

REACTION SCHEME m/ R RzNH R \NAN N O e" 0 Br Rf K OH H The following examples further illustrate this invention:

EXAMPLE 1 Preparation of Adenosine-5'-(N-Ethyl) Carboxamide Freshly prepared 2',3'-isopropylidene adenosine-5-carboxylic acid chloride (prepared from 6.4 g. of 2',3-isopropylidene-S-carboxylic acid) was stirred with excess of dry liquid ethyl amine at 50 to -35. The clear red-orange solution was allowed to warm up to room temperature and kept at this temperature for 15 hours. At the end of this period the excess of ethyl amine had evaporated otf. The residue was trituratcd with cold aqueous NaHCO solution. The white precipitate was filtered off and washed with a small amount of cold water to yield 3.1 g. (44.5%) of crude 2',3'-isopropylidene-5- [(N-ethyl)-carboxamide], m.p. 225227. Rf: 0.72 (silicagel) system: n-BuOH:H O:NH OH (86:14:5). This amide was mixed with 80 ml. of IN.HCl and kept at 65 for 45 minutes. The acidic solution was then cooled and basified with Nal-ICO The mixture was then evaporated to dryness under reduced pressure and the residue recrystallized twice from absolute ethanol and finally from water. The White crystalline product was dried in vacuo for 2 days over P at 7078 to give 0.9 g. (32%) of adenosine-5'-[N-ethyl)-carboxamide] which melted slowly at 13-6172 and solidified again at 148- 150 and finally melted at 246-247 (sharp). [a] -163 (C. 0.92 in IN.HCl); R 0.51 (silicagel). System: n-BuOH:H O:NH OI-I (86:14:05); NMR (deuterated DMSO) peaks (in p.p.m.) at 5.6 (2'-OH, 3'-OH); 7.4 (6C-NH 8.8 (CONH); 3.2 (CH CH Analysis.Calcd. for C H N O H O: C, 44.17; H, 5.53; N, 25.76. Found: C, 44.33; H, 6.01; N, 25.78.

EXAMPLE 2 Adenosine-5'-(N allyl)carboxamide, m.p. 223-24 dec., was prepared according to the method of Example 1, using allyl amine in place of ethyl amine.

Analysis.-Calcd. for C H N O .H O: C, 46.20; H, 5.36; N, 24.82; 0, 23.62. Found: C, 46.26; H, 5.58; N, 24.92; 0, 24.00.

EXAMPLE 3 Adenosne-5'-(N-cyclobutyl)carboxamide, m.p. 235- 37" dec., was prepared according to the method of Example 1 using cyclobutylamine in place of ethylamine.

Analysis.Calcd. for C H N O C, 50.30; H, 5.42; N, 25.14. Found: C, 50.52; H, 5.56; N, 24.72.

4 EXAMPLE 4 1,N -Etheno Adenosine-5'-(N-Allyl) Carboxamide Chloroacetaldehyde (26.0 g.; 0.1 mole of 30% aqueous solution) was added to a stirred suspension of adenosine5-(N-allyl) carboxamide (3.3 g.; 0.01 mole) in water ml.) containing a few drops of acetic acid at 50 C. In a few minutes the solid dissolved. After 17 hours at 50 C., the reaction solution gave only one fluorescent spot on the TLC paper. The cloudy reaction mixture was evaporated under reduced pressure. The oily residue solidified on trituration with acetone-ether. The amorphous solid, so obtained, was taken up in a large volume of methanol and stirred with Rexyn-203 [OH]. The methanolic solution was concentrated. Recrystallization of the residue gave the pure product, m.p. 242-244".

Analysis.Calcd. for C H N O C, 52.32; H, 4.68; N, 24.41. Found: C, 52.71; H, 4.69; N, 24.33.

EXAMPLE 5 1,N -etheno adenosine-5'-(N-cyclobutyl) carboxamide, m.p. 261-2-62, was prepared according to the method of Example 4 from adenosine-5'-(N-cyclobutyl) carboxamide and chloro-acetaldehyde.

AnaIysis.Calcd. for C H N O C, 53.63; H, 5.06; N, 23.45. Found: C, 53.21; H, 5.18; N, 23.04.

EXAMPLE 6 1,N -etheno adenosine-5-(N-ethyl) carboxamide, m.p. 252-254, was prepared according to the method of Example 4 from adenosine-5-(N-ethyl) carboxamide.

Analysis.Calcd. for C H N O C, 50.60; H, 4.85; N, 25.29. Found: C, 50.27; H, 4.85; N, 25.07.

EXAMPLE 7 Tablets containing 25 mg. of 1,N -etheno adenosine-5'- (N-allyl) carboxamide and having the following composition are prepared according to methods well known in the art.

Mg. 1,N -etheno adenosine-5'-(N-allyl) carboxamide 10 Starch 10 Colloidal silica 3 Magnesium stearate 2 wherein R and R each are hydrogen, loweralkyl, a cycloalkyl of 3 to 6 carbon atoms, loweralkenyl or lower- 5 alkynyl and R and R each hydrogen, acetyl, propionyl, butyryl, or R and R taken together form an isopropylidene or benzylidene moiety; and the pharmaceutically acceptable acid addition salts thereof.

2. A compound in accordance with Claim 1, 1,N- 5

etheno adenosine-5'-(N-allyl) carboxamide.

3. A compound in accordance with Claim 1, 1,N etheno aden0sine-$-(N-cyclobutyl) carboxamide.

4. A compound in accordance with Claim 1, LN- etheno adenosine-5'-(N-ethyl) carboxamide.

6 References Cited UNITED STATES PATENTS 3,551,409 12/1970 Kampe et al 2602l1.5 R 3,697,504 10/ 1972 Schmidt 260211.5 R

JOHNNIE R. BROWN, Primary Examiner US. Cl. X.R. 424-180 

